This proposal combines behavioral, biochemical and molecular approaches to examine the neurobiological influence of leptin on relapse to cocaine-seeking. The interaction between leptin, a peripheral hormone produced in fat cells, and relapse of cocaine-seeking could inform our understanding of peripheral influence on drug addiction and provide valuable treatment options. Preliminary data suggest that infusions of leptin may attenuate cocaine-seeking behavior in rats, while a reduction of leptin receptors in the ventral tegmental area (VTA) results in persistent cocaine-seeking. Rats press a lever for an infusion of cocaine that is paired with a tone-light cue. Cues have been shown to be strong mediators of craving, and even relapse, in both humans and animals. After learning to press for cocaine, the drug is removed and rats must learn that the lever press no longer results in drug delivery. It is hypothesized that leptin decreases cocaine-seeking only when lever pressing is paired with the cue as a result of a novel biochemical response to leptin. Behavioral experiments will investigate whether leptin decreases the value of the cue to attenuate cocaine-seeking behavior in extinction. On a biochemical and molecular level, processes involved with synaptic plasticity (specifically an increase in the glutamatergic AMPA receptor subunit GluR1) will be assayed at early and late timepoints after leptin infusion and exposure to cues associated with cocaine. Animal research suggests that manipulation of leptin in cocaine addicts may be a new pharmacological target for the treatment of cocaine dependence. Meanwhile, this project seeks to identify the neurobiological mechanisms in behavior and in plasticity underlying the effect of leptin on relapse to cocaine-seeking behavior in rats. Relevance to public health: Addiction to drugs of abuse can result in serious health consequences, loss of job, family and life;while addicts may want, and may even attempt to quit taking drugs, relapse is a persistent problem. However, few pharmacological interventions have proved helpful in preventing relapse, and craving for the drug, in a clinical population. Research from this proposal may provide justification for clinical trials to evaluate whether leptin can decrease cocaine craving and prevent relapse in human addicts.